Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–antagonists (e.g., full agonists and silent antagonists), SERMs are more tissue-specific, allowing them to selectively inhibit or stimulate estrogen-like action in various tissues.
Medical uses SERMs are used for various estrogen-related diseases, including treatment of ovulatory dysfunction in the management of infertility treatment, prevention of postmenopausal osteoporosis, treatment and risk reduction of breast cancer, and treatment of dyspareunia due to menopause. SERMs are also used in combination with conjugated estrogens indicated for the management of estrogen deficiency symptoms and of vasomotor symptoms associated with menopause.
SERMs are also being explored for gender-affirming hormone therapy in some non-binary transgender individuals that were assigned male at birth. Unlike full estrogen receptor agonists like estradiol which cause the broad development of feminine secondary sex characteristics, SERMs can be used to achieve partial feminization in individuals who wish to develop certain feminine traits such as softer skin and feminine body fat distribution without significant breast growth while avoiding the hypogonadic symptoms associated with suppressing testosterone alone. Unlike bioidentical estrogens, SERMs themselves do not suppress testosterone production by downregulating the HPG axis and therefore are used alongside antiandrogens such as cyproterone acetate or spironolactone, or GnRH agonists. The off-label use of SERMs for gender-affirming hormone therapy is still experimental and uncommon as there is limited research into efficacy including the degree of physical effects and long-term safety, especially there is little data regarding extended use.
Examples
Tamoxifen is a first-line hormonal treatment for ER-positive metastatic breast cancer. It is used for breast cancer risk reduction in women at high risk, and as adjuvant treatment for axillary node-negative and node-positive ductal carcinoma in situ. Tamoxifen treatment is also used for the treatment of osteoporosis and blood lipids in postmenopausal women. Adverse effects of tamoxifen include hot flashes and an increase in the risk of developing endometrial cancer compared to women of similar age.
Toremifene, a chlorinated tamoxifen derivative developed to avoid hepatic carcinomas, was associated with fewer DNA adducts in the liver than tamoxifen in preclinical studies. It is used as endocrine therapy for women with estrogen or progesterone receptor-positive, stage 4 or recurrent metastatic breast cancer and has demonstrated similar efficacy compared to tamoxifen as adjuvant treatment of breast cancer and in the treatment of metastatic breast cancer.
Raloxifene is used for the prevention and treatment of postmenopausal osteoporosis and breast cancer prevention in high-risk postmenopausal women with osteoporosis. Preclinical and clinical reports suggest that it is considerably less potent than estrogen for the treatment of osteoporosis. It is associated with an acceptable endometrial profile and has not demonstrated tamoxifen-like effects on the uterus, but has been associated with adverse effects such as venous thromboembolism and vasomotor symptoms, including hot flushes.
Ospemifene is an analogous metabolite of toremifene. Unlike tamoxifen, toremifene is not a rat hepatocarcinogen, and therefore ospemifene would also be a safer SERM than tamoxifen. It is used for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy associated with menopause. Clinical data on breast cancer are not available, but both in vitro and in vivo data suggest that ospemifene may have chemopreventive activity in breast tissue.
Bazedoxifene is used for treatment of osteoporosis in postmenopausal women at increased risk of fracture. It has been shown to be relatively safe and well-tolerated. It shows no breast or endometrial stimulation and in the first two years the small increase is better in venous thromboembolism, and similar in the long term to other SERMs. The advantage of bazedoxifene over raloxifene is that it increases endothelial nitric oxide synthase activity and does not antagonize the effect of 17β-estradiol on vasomotor symptoms.
The first tissue-selective estrogen complex (TSEC) combines conjugated estrogens and the SERM bazedoxifene to blend their activities. The combination therapy is used in the treatment of moderate to severe vasomotor symptoms associated with menopause, prevention of postmenopausal osteoporosis as well as treatment of estrogen deficiency symptoms in non-hysterectomized postmenopausal women. The combination allows for the benefits of estrogen with regard to relief of vasomotor symptoms without estrogenic stimulation of the endometrium.
SERMs have also been used in hormone replacement therapy by some transgender people.
DHED is a centrally selective, orally active prodrug of estradiol.
Available forms SERMs marketed for clinical or veterinary use Name Brand name Approved uses Launch Notes Anordrin Zi Yun Emergency contraception 1970s Only in China, combined with mifepristone Bazedoxifene Duavee Osteoporosis prevention 2013 Combined with conjugated estrogens Broparestrol Acnestrol Dermatology; Breast cancer treatment 1970s Discontinued Clomifene Clomid Female infertility 1967 Cyclofenil Sexovid Female infertility; Menopausal symptoms 1970 Mostly discontinued Lasofoxifene Fablyn Osteoporosis prevention, treatment; Vaginal atrophy 2009 Only in Lithuania and Portugal Ormeloxifene Saheli Hormonal contraception 1991 Only in India Ospemifene Osphena Dyspareunia due to vaginal atrophy 2013 Raloxifene Evista Osteoporosis prevention, treatment; Breast cancer prevention 1997 Tamoxifen Nolvadex Breast cancer treatment 1978 Toremifene Fareston Breast cancer treatment 1997 Sources: See individual articles.
Pharmacology
Pharmacodynamics
SERMs are competitive partial agonists of the ER. Different tissues have different degrees of sensitivity to the activity of endogenous estrogens, so SERMs produce estrogenic or antiestrogenic effects depending on the tissue in question, as well as the percentage of intrinsic activity (IA) of the SERM. An example of a SERM with high IA and thus mostly estrogenic effects is chlorotrianisene, while an example of a SERM with low IA and thus mostly antiestrogenic effects is ethamoxytriphetol. SERMs like clomifene and tamoxifen are comparatively more in the middle in their IA and their balance of estrogenic and antiestrogenic activity. Raloxifene is a SERM that is more antiestrogenic than tamoxifen; both are estrogenic in bone, but raloxifene is antiestrogenic in the uterus while tamoxifen is estrogenic in this part of the body.
Selective estrogen receptor degraders are also tissue-selectively estrogenic/anti-estrogenic, but not included in this table.
Binding site
SERMs act on the estrogen receptor (ER), which is an intracellular, ligand-dependent transcriptional activator and belongs to the nuclear receptor family. Two different subtypes of ER have been identified, ERα and ERβ. ERα is considered the main medium where estrogen signals are transduced at the transcriptional level and is the predominant ER in the female reproductive tract and mammary glands while ERβ is primarily in vascular endothelial cells, bone, and male prostate tissue. ERα and ERβ concentration are known to be different in tissues during development, aging or disease state. Many characteristics are similar between these two types such as size (~600 and 530 amino acids) and structure. ERα and ERβ share approximately 97% of the amino-acid sequence identity in the DNA-binding domain and about 56% in the ligand-binding domain. The main difference of the ligand-binding domains is determined by Leu-384 and Met-421 in ERα, which are replaced by Met-336 and Ile-373, respectively, in ERβ. The variation is greater on the N-terminus between ERα and ERβ.
The DNA-binding domain consists of two subdomains. One with a proximal box that is involved in DNA recognition while the other contains a distal box responsible for DNA-dependent, DNA-binding domain dimerization. The proximal box sequence is identical between ERα and ERβ, which indicates similar specificity and affinity between the two subgroups. DNA-binding domain's globular proteins contain eight cysteines and allow for a tetrahedral coordination of two zinc ions. This coordination makes the binding of ER to estrogen response elements possible. The ligand-binding domain is a globular, three-layered structure made of 11 helixes and contains a pocket for the natural or synthetic ligand. Influencing factors for binding affinity are mainly the presence of a phenol moiety, molecular size and shape, double bonds and hydrophobicity.
The differential positioning of the activating function 2 (AF-2) helix 12 in the ligand-binding domain by the bound ligand determines whether the ligand has an agonistic and antagonistic effect. In agonist-bound receptors, helix 12 is positioned adjacent to helices 3 and 5. Helices 3, 5, and 12 together form a binding surface for an NR box motif contained in coactivators with the canonical sequence LXXLL (where L represents leucine or isoleucine and X is any amino acid). Unliganded (apo) receptors or receptors bound to antagonist ligands turn helix 12 away from the LXXLL-binding surface that leads to preferential binding of a longer leucine-rich motif, LXXXIXXX(I/L), present on the corepressors NCoR1 or SMRT. In addition, some cofactors bind to ER through the terminals, the DNA-binding site or other binding sites. Thus, one compound can be an ER agonist in a tissue rich in coactivators but an ER antagonist in tissues rich in corepressors.
Mechanism of action
Estrogenic compounds span a spectrum of activity, including: Full agonists (agonistic in all tissues), such as the natural endogenous hormone estradiol. Mixed agonists/antagonistic (agonistic in some tissues while antagonistic in others), such as tamoxifen (a SERM). Pure antagonists (antagonistic in all tissues), such as fulvestrant.
SERMs are known to stimulate estrogenic actions in tissues such as the liver, bone and cardiovascular system but known to block estrogen action where stimulation is not desirable, such as in the breast and the uterus. This agonistic or antagonistic activity causes varied structural changes of the receptors, which results in activation or repression of the estrogen target genes. SERMs interact with receptors by diffusing into cells and their binding to ERα or ERβ subunits, which results in dimerization and structural changes of the receptors. This makes it easier for the SERMs to interact with estrogen response elements which leads to the activation of estrogen-inducible genes and mediating the estrogen effects.
SERMs unique feature is their tissue- and cell-selective activity. There is growing evidence to support that SERM activity is mainly determined by selective recruitment of corepressors and coactivators to ER target genes in specific types of tissues and cells. SERMs can impact coactivator protein stability and can also regulate coactivator activity through post-translational modifications such as phosphorylation. Multiple growth signaling pathways, such as HER2, PKC, PI3K and more, are downregulated in response to anti-estrogen treatment. Steroid receptor coactivator 3 (SRC-3) is phosphorylated by activated kinases that also enhance its coactivator activity, affect cell growth and ultimately contribute to drug resistance.